The advent of highly active anti-retroviral therapy (HAART) has reduced the incidence of HIV-1 associated dementia (HIV-D); however, the prevalence has risen, as HIV-1-infected individuals are now living longer with AIDS. The initiation of HAART therapy in patients exhibiting neurocognitive abnormalities has often demonstrated dramatic benefits, despite poor penetrance of anti-retroviral drugs across the blood brain barrier (BBB). Our major hypothesis put forth in this application is that alterations in monocyte/macrophage (MF) homeostasis, which leads to the expansion of a more invasive monocyte subset that is able to enter the CNS compartment in HIV-D, is responsive to HAART. CD163, a hemoglobin/haptoglobin scavenger receptor, has been reported by several groups as an identifying marker of the immunosuppressive macrophage type 2 (MF- 2). We observed significant accumulation of CD163+/CD16+ MFs in the CNS of patients with HIV encephalopathy (HIVE), the neuropathology of HIV-D, located perivascularly, within nodular lesions and in the brain parenchyma. These cells are the major reservoir of productive HIV-1 infection in the CNS. In a separate study, we found an increase in the percent frequency of circulating CD163+/CD16+ monocytes in HIV-1 infected individuals with detectable viral loads when compared with HIV-1 infected persons under successful pharmacological intervention and seronegative individuals. Moreover, expansion of this monocyte subset correlates strongly with viral load and CD4+ T cell loss This subset, which is CD163+/CD16+, may be more permissive to HIV-1 infection and contribute to the development of cognitive dysfunction by bringing virus into the CNS as well as through secreted factors and by-products associated with their activation status. We further hypothesize that the reduction in the incidence of HIV-D in the HAART era is, at least in part, reflective of the ability of HAART to restore monocyte/ MF homeostasis. The studies proposed in this application have three Specific Aims. Specific Aim 1 will test the hypothesis that monocyte/MF homeostasis is dysregulated in HIV-1 infected individuals, which is attenuated or reversed by successful HAART therapy. Specific Aim 2 Specific will test the hypothesis that the CD163+/CD16+ perivascular and parenchymal MFs that accumulate in the CNS in HIV-1 infected individuals with encephalopathy exhibit immune polarization, consistent with altered monocyte/MF homeostasis. Finally, Specific Aim 3 will test the hypothesis that monocyte subset homeostasis is altered by HIV-1 infection in vivo and in vitro. The studies proposed in this application should provide novel insights regarding the role of altered monocyte/ MF homeostasis in HIV induced neurocognitive disorders.